Osteoporosis is a major clinical and public health problem characterized by a loss of bone mineral density (BMD) and a resultant increase in the risk of disabling fractures. Although osteoporosis is commonly associated with women, men also experience substantial bone loss with aging and osteoporosis is an immense health problem among older men. In contrast to our understanding of osteoporosis in women, much less is known about the etiology of bone loss and osteoporosis in men. The goal of the current application is to advance our understanding of the genetic regulation of BMD and the loss of BMD with aging among older men. To achieve these goals, we are proposing to investigate the association of inherited variation in Wnt signaling pathway genes and BMD and the rate of loss in BMD in 9,914 older men of Caucasian and African ancestry. We will test for associations of BMD and rate of decline in BMD with single genes, evaluate selected gene-gene interactions, and investigate the functional consequences of selected genetic variants in an in vitro human osteoblast model. Understanding the impact of genetic variation in the Wnt signaling pathway on BMD in men will yield fundamental insight on the molecular mechanisms underlying osteoporosis and may also have implications for drug development and pharmacogenomic-based targeting of therapies to individuals at the greatest risk of disease. PUBLIC HEALTH RELEVANCE: Osteoporosis is a major clinical and global public health problem. In sharp contrast to our understanding of the etiology and prevention of osteoporosis in women, there is a paucity of information about bone health in men. Our proposed study seeks to identify inherited genetic variations responsible for bone loss and osteoporosis in men.